tbuckley/cabot-search huggingface dataset:
Audit of Data Sharing by Pharmaceutical Companies for Anticancer Medicines Approved by the US Food and Drug Administration
Authors: Natansh D. Modi, Ahmad Y. Abuhelwa, Ross A. McKinnon, Alan V. Boddy, Mark Haseloff, Michael D. Wiese, Tammy C. Hoffmann, Eric D. Perakslis, Andrew Rowland, Michael J. Sorich, Ashley M. Hopkins
Journal: JAMA Oncology (2022)

Emerging policies drafted by the pharmaceutical industry indicate that they will transparently share clinical trial data. These data offer an unparalleled opportunity to advance evidence-based medicine and support decision-making.To evaluate the eligibility of independent, qualified researchers to access individual participant data (IPD) from oncology trials that supported US Food and Drug Administration (FDA) approval of new anticancer medicines within the past 10 years.In this quality improvement study, a cross-sectional analysis was performed of pivotal clinical trials whose results supported FDA-approved anticancer medicines between January 1, 2011, and June 30, 2021. These trials' results were identified from product labels.Eligibility for IPD sharing was confirmed by identification of a public listing of the trial as eligible for sharing or by receipt of a positive response from the sponsor to a standardized inquiry.The main outcome was frequency of IPD sharing eligibility. Reasons for data sharing ineligibility were requested and collated, and company-, drug-, and trial-level subgroups were evaluated and presented using χ2 tests and forest plots.During the 10-year period examined, 115 anticancer medicines were approved by the FDA on the basis of evidence from 304 pharmaceutical industry-sponsored trials. Of these trials, 136 (45%) were eligible for IPD sharing and 168 (55%) were not. Data sharing rates differed substantially among industry sponsors, with the most common reason for not sharing trial IPD being that the collection of long-term follow-up data was still ongoing (89 of 168 trials [53%]). Of the top 10 anticancer medicines by global sales, nivolumab, pembrolizumab, and pomalidomide had the lowest eligibility rates for data sharing (<10% of trials).There has been a substantial increase in IPD sharing for industry-sponsored oncology trials over the past 5 years. However, this quality improvement study found that more than 50% of queried trials for FDA-approved anticancer medicines were ineligible for IPD sharing. Data accessibility would be substantially improved if, at the time of FDA registration of a medicine, all data that support the registration were made available.
Clinical features and novel presentations of human monkeypox in a central London centre during the 2022 outbreak: descriptive case series
Authors: Aatish Patel, Julia Bilinska, Jerry C H Tam, Dayana Da Silva Fontoura, Claire Y Mason, Anna Daunt, Luke B Snell, Jamie Murphy, Jack Potter, Cecilia Tuudah, Rohan Sundramoorthi, Movin Abeywickrema, Caitlin Pley, Vasanth Naidu, Gaia Nebbia, Emma Aarons, Alina Botgros, Sam T Douthwaite, Claire van Nispen tot Pannerden, Helen Winslow, Aisling Brown, Daniella Chilton, Achyuta Nori
Journal: BMJ (2022)

Abstract Objective To characterise the clinical features of monkeypox infection in humans. Design Descriptive case series. Setting A regional high consequences infectious disease centre with associated primary and secondary care referrals, and affiliated sexual health centres in south London between May and July 2022. Participants 197 patients with polymerase chain reaction confirmed monkeypox infection. Results The median age of participants was 38 years. All 197 participants were men, and 196 identified as gay, bisexual, or other men who have sex with men. All presented with mucocutaneous lesions, most commonly on the genitals (n=111 participants, 56.3%) or in the perianal area (n=82, 41.6%). 170 (86.3%) participants reported systemic illness. The most common systemic symptoms were fever (n=122, 61.9%), lymphadenopathy (114, 57.9%), and myalgia (n=62, 31.5%). 102/166 (61.5%) developed systemic features before the onset of mucocutaneous manifestations and 64 (38.5%) after (n=4 unknown). 27 (13.7%) presented exclusively with mucocutaneous manifestations without systemic features. 71 (36.0%) reported rectal pain, 33 (16.8%) sore throat, and 31 (15.7%) penile oedema. 27 (13.7%) had oral lesions and 9 (4.6%) had tonsillar signs. 70/195 (35.9%) participants had concomitant HIV infection. 56 (31.5%) of those screened for sexually transmitted infections had a concomitant sexually transmitted infection. Overall, 20 (10.2%) participants were admitted to hospital for the management of symptoms, most commonly rectal pain and penile swelling. Conclusions These findings confirm the ongoing unprecedented community transmission of monkeypox virus among gay, bisexual, and other men who have sex with men seen in the UK and many other non-endemic countries. A variable temporal association was observed between mucocutaneous and systemic features, suggesting a new clinical course to the disease. New clinical presentations of monkeypox infection were identified, including rectal pain and penile oedema. These presentations should be included in public health messaging to aid early diagnosis and reduce onward transmission.
Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic
Authors: Nicholas A Kennedy, Malik Janjua, Neil Chanchlani, Simeng Lin, Claire Bewshea, Rachel Nice, Timothy J McDonald, Cressida Auckland, Lorna W Harries, Merlin Davies, Stephen Michell, Klaartje B Kok, Christopher A Lamb, Philip J Smith, Ailsa L Hart, Richard CG Pollok, Charlie W Lees, Rosemary J Boyton, Daniel M Altmann, Shaji Sebastian, Nicholas Powell, James R Goodhand, Tariq Ahmad
Journal: Gut (2022)

Objective Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD. Design Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study. Results Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p&lt;0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p&lt;0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p&lt;0.0001). Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups. Conclusions Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant. Trial registration number ISRCTN45176516 .
Last Train Home
Authors: David H. Xiang
Journal: JAMA Oncology (2022)

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Efficient in vivo base editing via single adeno-associated viruses with size-optimized genomes encoding compact adenine base editors
Authors: Jessie R. Davis, Xiao Wang, Isaac P. Witte, Tony P. Huang, Jonathan M. Levy, Aditya Raguram, Samagya Banskota, Nabil G. Seidah, Kiran Musunuru, David R. Liu
Journal: Nature Biomedical Engineering (2022)

The viral delivery of base editors has been complicated by their size and by the limited packaging capacity of adeno-associated viruses (AAVs). Typically, dual-AAV approaches based on trans-splicing inteins have been used. Here we show that, compared with dual-AAV systems, AAVs with size-optimized genomes incorporating compact adenine base editors (ABEs) enable efficient editing in mice at similar or lower doses. Single-AAV-encoded ABEs retro-orbitally injected in mice led to editing efficiencies in liver (66%), heart (33%) and muscle (22%) tissues that were up to 2.5-fold those of dual-AAV ABE8e, and to a 93% knockdown (on average) of human PCSK9 and of mouse Pcsk9 and Angptl3 in circulation, concomitant with substantial reductions of plasma cholesterol and triglycerides. Moreover, three size-minimized ABE8e variants, each compatible with single-AAV delivery, collectively offer compatibility with protospacer-adjacent motifs for editing approximately 82% of the adenines in the human genome. ABEs encoded within single AAVs will facilitate research and therapeutic applications of base editing by simplifying AAV production and characterization, and by reducing the dose required for the desired level of editing.
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins
Authors: Museer A. Lone, Mari J. Aaltonen, Aliza Zidell, Helio F. Pedro, Jonas A. Morales Saute, Shalett Mathew, Payam Mohassel, Carsten G. Bönnemann, Eric A. Shoubridge, Thorsten Hornemann
Journal: Journal of Clinical Investigation (2022)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS-expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.
Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment
Authors: William L. Hwang, Karthik A. Jagadeesh, Jimmy A. Guo, Hannah I. Hoffman, Payman Yadollahpour, Jason W. Reeves, Rahul Mohan, Eugene Drokhlyansky, Nicholas Van Wittenberghe, Orr Ashenberg, Samouil L. Farhi, Denis Schapiro, Prajan Divakar, Eric Miller, Daniel R. Zollinger, George Eng, Jason M. Schenkel, Jennifer Su, Carina Shiau, Patrick Yu, William A. Freed-Pastor, Domenic Abbondanza, Arnav Mehta, Joshua Gould, Conner Lambden, Caroline B. M. Porter, Alexander Tsankov, Danielle Dionne, Julia Waldman, Michael S. Cuoco, Lan Nguyen, Toni Delorey, Devan Phillips, Jaimie L. Barth, Marina Kem, Clifton Rodrigues, Debora Ciprani, Jorge Roldan, Piotr Zelga, Vjola Jorgji, Jonathan H. Chen, Zackery Ely, Daniel Zhao, Kit Fuhrman, Robin Fropf, Joseph M. Beechem, Jay S. Loeffler, David P. Ryan, Colin D. Weekes, Cristina R. Ferrone, Motaz Qadan, Martin J. Aryee, Rakesh K. Jain, Donna S. Neuberg, Jennifer Y. Wo, Theodore S. Hong, Ramnik Xavier, Andrew J. Aguirre, Orit Rozenblatt-Rosen, Mari Mino-Kenudson, Carlos Fernandez-del Castillo, Andrew S. Liss, David T. Ting, Tyler Jacks, Aviv Regev
Journal: Nature Genetics (2022)
Lung allograft transbronchial cryobiopsy for critical ventilated patients: a randomised trial
Authors: Karina Loor, Mario Culebras, Irene Sansano, Antonio Álvarez, Judith Sacanell, Marina García-de-Acilu, Cristina Berastegui, Eva Polverino, David Clofent, Javier de Gracia
Journal: European Respiratory Journal (2022)

Background Transbronchial lung cryobiopsy is an emerging technique for diagnosing pulmonary rejection. However, no prospective studies of this procedure for critically ill lung transplant recipients who require mechanical ventilation in the intensive care unit (ICU) have been performed. Methods From March 2017 to January 2020, we performed a prospective, randomised, comparative study to assess the diagnostic yield, histological quality and safety of transbronchial lung biopsy using biopsy forceps, a 1.9-mm cryoprobe or a 2.4-mm cryoprobe. Results 89 out of 129 consecutive transbronchial biopsy procedures (forceps group, 28 procedures; 1.9-mm cryoprobe group, 31 procedures; 2.4-mm cryoprobe group, 30 procedures) were randomised. Compared with lung samples from the forceps and 1.9-mm cryoprobe groups, lung samples from the 2.4-mm cryoprobe group allowed the most definitive diagnoses (p&lt;0.01 and p=0.02, respectively), the most diagnoses of acute lung rejection (p&lt;0.01 and p=0.01, respectively) and the most diagnoses of rejection severity (p&lt;0.01 and p&lt;0.01, respectively). These samples were larger (p&lt;0.01 and p=0.04, respectively), had the most adequate alveolar tissue (p&lt;0.01 and p=0.02, respectively), had more vessels per procedure (p&lt;0.01 and p=0.01, respectively) and had no significant crush artefacts. Moderate bleeding was observed in 23% of cases (p=0.01 and p=0.08, respectively). No severe bleeding was observed. Conclusions Transbronchial lung biopsy using a 2.4-mm cryoprobe allows the safe collection of lung tissue samples from critically ill lung transplant recipients who require mechanical ventilation in the ICU and has good diagnostic performance.
Reply: COVID-19 drug research and the cohort multiple randomised controlled trial design
Authors: Raphaël Porcher, Philippe Ravaud, Matthieu Resche-Rigon, Pierre-Louis Tharaux, Xavier Mariette, Olivier Hermine
Journal: European Respiratory Journal (2022)

We read with interest the comment of R. Dal-Ré on the CORIMUNO-19 trials design [1–5]. The key argument is that the cohort multiple randomised controlled trial (cmRCT) design implies an alteration of the informed process that can only be justified if three requirements are fulfilled: the research has important social value, it poses no more than minimal risks to participants, and it would be impracticable to carry out without consent process modification [6]. R. Dal-Ré acknowledges that the first two requirements were fulfilled for CORIMUNO-19 trials, but argues that, given the huge number of patients hospitalised with severe or critical coronavirus disease 2019 (COVID-19) in March 2020, trials would have been feasible without consent modification. The use of cohort multiple randomised controlled trials and epidemic crises https://bit.ly/39Obd4N
Detection of COPD in the SUMMIT Study lung cancer screening cohort using symptoms and spirometry
Authors: Sophie Tisi, Jennifer L. Dickson, Carolyn Horst, Samantha L. Quaife, Helen Hall, Priyam Verghese, Kylie Gyertson, Vicky Bowyer, Claire Levermore, Anne-Marie Mullin, Jonathan Teague, Laura Farrelly, Arjun Nair, Anand Devaraj, Allan Hackshaw, John R. Hurst, Sam M. Janes
Journal: European Respiratory Journal (2022)

Background COPD is a major comorbidity in lung cancer screening (LCS) cohorts, with a high prevalence of undiagnosed COPD. Combining symptom assessment with spirometry in this setting may enable earlier diagnosis of clinically significant COPD and facilitate increased understanding of lung cancer risk in COPD. In this study, we wished to understand the prevalence, severity, clinical phenotype and lung cancer risk of individuals with symptomatic undiagnosed COPD in a LCS cohort. Methods 16 010 current or former smokers aged 55–77 years attended a lung health check as part of the SUMMIT Study. A respiratory consultation and spirometry were performed alongside LCS eligibility assessment. Those with symptoms, no previous COPD diagnosis and airflow obstruction were labelled as undiagnosed COPD. Baseline low-dose computed tomography (LDCT) was performed in those at high risk of lung cancer (PLCO m2012 score ≥1.3% and/or meeting USPSTF 2013 criteria). Results Nearly one in five (19.7%) met criteria for undiagnosed COPD. Compared with those previously diagnosed, those undiagnosed were more likely to be male (59.1% versus 53.2%; p&lt;0.001), currently smoking (54.9% versus 47.6%; p&lt;0.001) and from an ethnic minority group (p&lt;0.001). Undiagnosed COPD was associated with less forced expiratory volume in 1 s impairment (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1 and 2: 85.3% versus 68.4%; p&lt;0.001) and lower symptom/exacerbation burden (GOLD A and B groups: 95.6% versus 77.9%; p&lt;0.001) than those with known COPD. Multivariate analysis demonstrated that airflow obstruction was an independent risk factor for lung cancer risk on baseline LDCT (adjusted OR 2.74, 95% CI 1.73–4.34; p&lt;0.001), with a high risk seen in those with undiagnosed COPD (adjusted OR 2.79, 95% CI 1.67–4.64; p&lt;0.001). Conclusions Targeted case-finding within LCS detects high rates of undiagnosed symptomatic COPD in those most at risk. Individuals with undiagnosed COPD are at high risk for lung cancer.
Bone marrow–confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia
Authors: Yang Mei, Kehan Ren, Yijie Liu, Annabel Ma, Zongjun Xia, Xu Han, Ermin Li, Hamza Tariq, Haiyan Bao, Xinshu Xie, Cheng Zou, Dingxiao Zhang, Zhaofeng Li, Lili Dong, Amit Verma, Xinyan Lu, Yasmin Abaza, Jessica K. Altman, Madina Sukhanova, Jing Yang, Peng Ji
Journal: Journal of Clinical Investigation (2022)

Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risk of progression to acute myeloid leukemia (AML). The mechanisms of transformation of MDS to AML are poorly understood, especially in relation to the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with oversecretion of proinflammatory cytokines. Here, we found that most of the DKO mice underwent leukemic transformation at 12-14 months of age. These mice showed myeloblast replacement of fibrotic bone marrow and widespread leukemic infiltration. Strikingly, depletion of IL-6 in these mice largely rescued the leukemic transformation and markedly extended survival. Single-cell RNA sequencing analyses revealed that DKO leukemic mice had increased monocytic blasts that were reduced with IL-6 knockout. We further revealed that the levels of surface and soluble IL-6 receptor (IL-6R) in the bone marrow were significantly increased in high-risk MDS patients. Similarly, IL-6R was also highly expressed in older DKO mice. Blocking of IL-6 signaling significantly ameliorated AML progression in the DKO model and clonogenicity of CD34-positive cells from MDS patients. Our study establishes a mouse model of progression of age-related MDS to AML and indicates the clinical significance of targeting IL-6 signaling in treating high-risk MDS.
Improved ventilatory efficiency to evidence haemodynamic improvement after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension
Authors: Simon Madoun, Nicolas Piliero, Alicia Guillien, Muriel Salvat, Frédéric Thony, Mathieu Finas, Caroline Augier, Hélène Bouvaist, Bruno Degano
Journal: European Respiratory Journal (2022)

<b>In contrast to the 6-minute walk test, the cardiopulmonary exercise test provides simple, non-invasive parameters that correlate with haemodynamic improvements in patients with chronic thromboembolic pulmonary hypertension undergoing balloon angioplasty</b>https://bit.ly/3uFp2cP
Relation of Change or Substitution of Low- and No-Calorie Sweetened Beverages With Cardiometabolic Outcomes: A Systematic Review and Meta-analysis of Prospective Cohort Studies
Authors: Jennifer J. Lee, Tauseef A. Khan, Nema McGlynn, Vasanti S. Malik, James O. Hill, Lawrence A. Leiter, Per Bendix Jeppesen, Dario Rahelić, Hana Kahleová, Jordi Salas-Salvadó, Cyril W.C. Kendall, John L. Sievenpiper
Journal: Diabetes Care (2022)

Adverse associations of low- and no-calorie sweetened beverages (LNCSB) with cardiometabolic outcomes in observational studies may be explained by reverse causality and residual confounding.